Monoclonal antibodies directed against protein antigens are used as probes to study antibody-protein interactions and structure-function relationships, and to study developmentally regulated antigens in normal and neoplastic development. In order to define the complementary structure of an antibody and a protein epitope as precisely as possible, antigenic regions and specific epitopes recognized by monoclonal antibodies to two well characterized proteins, lysozyme c and ovomucoid from avian egg white, are examined. Epitopes are mapped by comparing antibody reactivity with related proteins, and results to date have revealed significant relationships between antigenic and tertiary structure. The antibodies are analyzed structurally by sequencing, chain recombination studies, crystallography and computer modelling, and results to date suggest that properties of the antibody combining site in an anti-protein immunoglobulin may differ significantly from those of anti-hapten immunoglobulins. Structurally and functionally related antibodies are compared to determine genetic mechanisms underlying anti-protein specificity. Experiments are in progress to generate monoclonal antibodies to onc gene protein products; these antibodies will be used to study these proteins in normal and neoplastic B-cell development.